This proposal is a renewal of an ongoing collaborative program among investigators at the Massachusetts Institute of Technology (MIT) and New England Eye Center (NEEC). The program focuses on the development of optical coherence tomography (OCT) technology and its application to investigate structural alterations and blood flow impairment in age-related macular degeneration (AMD). Aim 1. Next Generation OCT Technology for Imaging Structure and Blood Flow in AMD. Task 1. We will develop ultrahigh speed, swept-source OCT angiography (SS-OCTA) operating at >1MHz A-scan rates (5-10 faster than commercial OCTA). Ultrahigh A- scan rates enable detection of subtle blood flow impairments and measurement of relative blood flow speeds that are not possible with commercial OCTA. Task 2. We will develop ultrahigh resolution spectral-domain OCT (SD-OCT) technology with a 2.5-3m axial resolution, higher A-scan rates, software motion correction and extended imaging range using dynamic depth-tracking. Ultrahigh resolution enables detection of subtle structural alterations in the photoreceptors/retinal pigment epithelium/Bruch's membrane (PR/RPE/BM), including basal deposits, which are potential early markers of disease. Task 3. We will develop software/hardware methods to enable simultaneous study of structure and blood flow. Aim 2. Imaging Structural Alterations and Blood Flow Impairment in Early and Intermediate AMD. Task 4. We will perform a cross-sectional SS-OCTA/SD-OCT study of eyes with early or intermediate AMD to investigate markers of CC flow impairment (e.g., CC flow deficits) and PR/RPE/BM structural alterations (e.g., basal deposit thicknesses), their mutual associations and association with drusen to establish in vivo analogues of histopathology findings. Task 5. We will perform a longitudinal SS-OCTA/SD-OCT study of eyes with intermediate AMD to investigate the spatiotemporal correlation of CC flow impairment and PR/RPE/BM alterations with development of nascent geographic atrophy (GA), non-exudative choroidal neovascularization (CNV) and late AMD (GA/exudative AMD) to elucidate pathogenesis and identify markers of progression. Aim 3. Imaging Structural Alterations and Blood Flow Impairment in GA. Task 6. We will perform a longitudinal SS-OCTA/SD-OCT study of GA eyes to investigate CC blood flow impairments and PR/RPE/BM alterations and their association with GA growth. Task 7. We will develop a model to predict the spatiotemporal progression of GA. Aim 4. Imaging Blood Flow Impairment in Non-Exudative CNV. Task 8. We will longitudinally study eyes with non-exudative CNV, a known risk-factor for exudation. SS-OCTA with variable interscan time analysis will be used to study relative blood flow speeds and other flow parameters (e.g., shear stress) as possible predictors of time-to-exudation. The program develops and applies new imaging technologies and methods that will enable the first integrated studies of blood flow impairment and structural alterations in AMD progression. The identification of markers of disease and progression can improve diagnosis, treatment monitoring and accelerate pharmaceutical development.